Understanding Amyloid Fibril Structures May Provide Treatment Pathway for Neurodegenerative Diseases

Illustration of amyloid plaques on a nerverticale cell
Illustration of amyloid plaques on a nerverticale cell.

Transactive response DNA-binding protein-43 (TDP-43) is a soluble protein that interacts with nucleic acids. However, in several neurodegenerative disorders, this protein forms large, harmful rope-like clumps. These abnormal structures, known as amyloid fibrils, are a signature of brain pathology in amyotrophic lateral sclerosis (ALS). Similar inclusions have also been found in several other disorders, including Alzheimer’s disease, cerebral age-related TDP-43 with sclerosis, dementia with Lewy bodies, hippocampal sclerosis, Huntington’s disease, and chronic traumatic encephalopathy.

By using cryo-electron microscopy, scientists at the Case Western Reserve University School of Medicine were able to determine the structures of TDP-43. This structural insight provides clues as to how these toxic proteins clump and spread between nerve cells in the brain. Their findings may pave the way for developing new therapeutics to treat diseases such as ALS and frontotemporal dementia (FTD).

Their findings are published in the journal Nature Communications, in a paper titled, “Cryo-EM structure of amyloid fibrils formed by the entire low complexity domain of TDP-43.”

“Amyotrophic lateral sclerosis and several other neurodegenerative diseases are associated with brain deposits of amyloid-like aggregates formed by the C-terminal fragments of TDP-43 that contain the low complexity domain of the protein,” wrote the researchers. “Here, we report the cryo-EM structure of amyloid formed from the entire TDP-43 low complexity domain in vitro at pH 4. This structure reveals single protofilament fibrils containing a large (139-residue), tightly packed core.”

“These devastating brain disorders that affect tens of thousands of Americans are on the rise worldwide, and there are no effective treatments to stop their progression,” stated Witold Surewicz, a professor in the department of physiology and biophysics at the School of Medicine and the study’s senior author.

The researchers analyzed thousands of images of fibrils formed in the test tube by the key fragment of TDP-43. They determined the complex architecture of these elongated structures at a resolution close to individual atoms. This structural insight revealed the nature of the template on which more copies of TDP-43 can lock.

The researchers also observed how the fibril structure could be controlled by amino acid mutations in TDP-43 linked to hereditary forms of ALS and FTD, as well as by aging-dependent modifications of the protein.

“The present structure for non-phosphorylated TDP-43 LCD fibrils provides a necessary foundation for future high-resolution structural studies with fibrils containing protein variants with different phosphorylation patterns,” concluded the researchers.

Qiuye Li, a graduate student and lead author commented: “This is really an exciting development because it reveals a mechanism for the growth of these toxic aggregates. This, in turn, provides important clues as to how these aggregates may spread between the cells in affected brains.”

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